6-methyl steroid derivatives and processes of preparing same



United States Patent 3,028,381 fi-METHYL STEROID DERIVATIVES ANDPROCESSES 0F PREPARING SAME Vladimir Petrow and David Morton Williamson,London,

England, assignors to The British Drug Houses Limited,

London, England, a British company No Drawing. Filed July 6, 1959, Ser.No. 824,961 Claims priority, application Great Britain July 9, 1958 6Claims. (Cl. 260-2395) This invention is for improvements in or relatingto organic compounds and has particular reference to the preparation ofnew 6:16-dimethylpregnane derivatives which are of value asintermediates in the preparation of 17a-hydroxyand 17a-acyloxy6:16-dimethyl derivatives of pregnane which are valuable asprogrestational agents.

In particular l7a-acetoxy-6a,IG-dimethylprogesterone is found to be 100times more potent than dimethisterone (6a,2l dimethylethisterone; 60:,21dimethylanhydrohydroxyprogesterone) in the Clauberg assay. Asdimethisterone (6a,21-dimethylethisterone) is known to be slightly morethan 10 times as active as anhydrohydroxyprogesterone (ethisterone) inthe Clauberg assay (David, Hartley, 'Millson and Petrow, J. Pharm.Pharmacol, 1957, 9, 929), it will be apparent to those skilled in theart that l7a-acetoxy-6al6-dimethylprogesterone is a proges-tationa1agent of quite unexpected and remarkable potency, and its preparation amatter of importance.

It is an object of the present invention to provide the new compounds3,8-hydroxyand 3fi-acyloxy- 6: 16-dimethylpregna-z16-dien-20-one (I; R=Hor an acyl group containing up to carbon atoms) OOMe The above compoundsare valuable and convenient starting materials for the preparation ofthe potent proges-tational agent 17a-acetoxy-6a,16-dimethylprogesterone.Their conversion into this progestational agent may be accomplished byconverting compound I into the 3-oxoderivative, 60::16-dimethylpregna-4: l6-dien-3 :20-dione forming the 16a,17u-epoxide,converting this 1641,17- epoxide into a 17a-hydroxy-16,8-halo-16a-methylintermediate by reaction with a halohydrin, reductively removing thehalogen atom and acetylatnig the tert.-hydrcxyl group at C The presentinvention also provides the intermediate pyrazolines 3fi-hydroxyand3fi-acyloxy-6-methyl-l6:17-

3,028,381 Patented Apr. 3, 1962 (2' 3' diazacyclopent-2-eno-pregn-5-en-20-one (III; R=H or acyl) 0 OMe Lu 1- CH2 Me I Me (III)According to the present invention there is provided a process for thepreparation of 3fi-hydroxy and 3f3-acyloxy-6: l6-dimethylpregna-5l6-dien-20-one which process comprises reacting the correspondingBfi-acyloxy or 313-hydroxy-6-methylpregna-5z l6-dien-20-one (IV) whereR=H or an acyl group containing up to 10 carbon atoms i A B0 Me '(IV)with diazomethane to yield the corresponding 16a,17u-

. methylene diazo derivative (III) or pyrazoline and thermallydecomposing the pyrazoline.

Addition of diazomethane to the starting material (IV) is preferablyperformed in an unreactive organic solvent such as diethyl ether and thereaction mixture allowed to stand at room temperature for periods of 16to 40 hours, and the pyrazoline subsequently isolated by removal of thesolvent by evaporation and crystallisation of the residue.

Decomposition of the pyrazoline (III) to yield the 6:l6-dimethylpregnane derivative (1) may readily be performed by heatingthe pyrazoline under reflux in an inert organic solvent of B.P.approximately the same as the MP. of the pyrazoline, such as dibutylether, for 3 to 5 hours. p-Cymene and ethylene glycol are other solventssuitable for efiecting this thermal decomposition.

Conversion of I (where R=acyl) into I (where R=H) may readily beeffected by alkaline hydrolysis, for example by heating the acylderivative with the carbonate or hydroxide of an alkali metal in anaqueous/ organic solvent mixture such as aqueous acetone or aqueoustert.- butanol.

Following is a description by way of example of methods of carrying theinvention into effect.

Example 1 3p -acetoxy-6-methy-l-16: 17-(2 3'-diazacyclopent-2-eno)-pregn-5-en-20-one (III; R=Ac):3fiacetoxy-6-methlypregna-5:l6-dien-20-one (IV) (20 gm.) was treatedwith a solution of diazomethane prepared from N-methyl-N-nitroso-toluene-p-sulphonamide gm.) in diethyl ether (750 mls.) andthe mixture was allowed to stand at room temperature overnight (16hours). Excess diazomethane was destroyed by addition of dilute aceticacid, and the ethereal layer washed with water, sodium bicarbonatesolution, water and dried. The ether was re- 3 moved under reduced.pressure and the residue crystallised from methanol to yield3,6-acetoxy-6-methyl-16:17- (2': 3' diazacyclopent 2-eno)-pregn-5-en-20-one (III; R=Ac), plates, M.P. 156 to 158 C. withdecomposition, l4 (c., 0.44 in chloroform).

35 acetoxy-6:16-dimethylpregna-5:16-dien-20-one (I; R=Ac): The foregoingpyrazoline (III; R=Ac) (20 gm.) was dissolved in dibutyl ether (200 ml.)and the solution heated under reflux for 3 hours. The dibutyl ether wasremoved under reduced pressure and the residue crystallised frommethanol to give 3,8-acetoxy-6: l6- dimethylpregna-S:l6-dien-20-one (I;R=Ac), plates, M.P. 158 to 160 C., 41 (c., 0.654 in chloroform),

A523? 251 my, e=8650 3 fi-hydroxy-6: 16-dimethylpregna-5 16-dien-20-one(I; R=H): The foregoing 3/3-acetoxy-6:16-dimethylpregna-5:16-dien-20-one (I; R=Ac) (2 gm.) was hydrolysed by heating underreflux with potassium hydroxide (2 gm.) in methanol (80 ml.) and water(20 ml.) for 1 hour. The mixture was poured into water and theprecipitate filtered off, washed with water, dried and crystallised frommethanol to give 3B-hydroxy-6:16-dimethylpregna- 5:16-dien-20-one (I;R=H), plates, M.P. 148 to 149 C., [aJ 99 (c., 0.292 in chloroform),

513? 251 to 253 m e 8806 Example 2 3ii-hydroxy-6: 16-dimethylpregna-5:16-dien-20-one (I; R=H): 3 3 hydroxy-6-methylpregna-5:16-dien-20-one(IV; R=H) (20 g.) was treated with an ethereal solution of diazomethanein the manner described in Example 1. The crude pyrazoline (III; R=H)thus obtained was dissolved in dibutyl ether (200 ml.) and the solutionheated under reflux for 3 hours. After removal of the dibutyl ether, theresidue was crystallised from methanol to give 3fi hydroxy-6:16-dimethylpregna-5: 16-dien ZO-one, M.P. 148 to 149. (3., identicalwith a specimen prepared as described above.

" We claim 1. 'A process for the preparation of 3fi-hydroxyand3,8}acyloxy-6: 16-dimethylpregna-5: 16-dien-2 0-one which processcomprises reacting the corrspondingBB-acyloxy or 38-hydroxy-6-methylpregna-5:16 dien-20one with diazomethane to yield thecorresponding 16a,17a-methylene diazo derivative and heating tothermally decompose said 1611,1704, methylene diazo derivative.

2. A process as claimed in claim 1 wherein the diazomethane in diethylether is added to the steroid starting material and the reaction mixtureallowedto stand at room temperature for periods of 16 to 40 hours.

3. A process as claimed in claim 1 wherein the 160:, Not-methylene diazoderivative is decomposed by heating under reflux in an inert organicsolvent of BF. approximately the same as the M.P. of the16a,17oc-m6thylene diazo derivative.

4. A process as claimed in claim 3 wherein the inert organic solvent isdibutyl ether and the heating under reflux is carried out for 3 to 5hours.

6. 3l3-hydroxyand 3B-acyloxy-6-methyl-16:17-(2:3- diazacyclopent-2-eno)-pregn-5-en-20-one Me COMe Me (In 40 where R=H or an aeyl groupcontaining up to 19 carbon atoms.

References Cited in the file of this patent IJNITED STATES PATENTSBeyler et a1. May 26, 1959 OTHER REFERENCES Journal of Chemical Society(1957), article by Burn et al., pages 40-94 relied on.

1. A PROCESS FOR THE PREPARATION OF 3B-HYDROXY-AND3B-ACYLOXY-6:16-DIMETHYLPREGNA-5:16-DIEN-20-ONE WHICH PROCESS COMPRISESREACTING THE CORRESPONDING 3-B-ACYLOXY OR3B-HYDROXY-6-METHYLPREGNA-5:16-DIEN-20-ONE WITH DIAZOMETHANE TO YEILDTHE CORRESPONDING 16A,17A-METHYLENE DIAZO DERIVATIVE AND HEATING TOTHERMALLY DECOMPOSE SAID 16A,17A, METHYLENE DIAZO DERIVATIVE. 6.3B-HYDROXY- AND3B-ACYLOXY-6-METHYL-16:17-(2'':3''DIAZACYCLOPENT-2''-ENO)-PREGN-5-EN-20-ONE